Certain substituted benzylamine derivatives; a new class of neuropeptide Y1 specific ligands

ABSTRACT

This invention encompasses compounds of formula (I) and the pharmaceutically ##STR1## acceptable salts thereof, wherein W,X,Y,A,T,R 1  -R 4 ,B,Ar,n and m are described herein and are useful in treating feeding disorders and certain cardiovascular diseases due to the binding of these compounds to human Neuropeptide Y1 receptors.

This application is the National Stage of International Application No.PCT/US95/14472 filed Nov. 7, 1995 which is a continuation-in-part ofU.S. application Ser. No. 478,383 filed Jun. 7, 1995, now abandoned,which is a continuation-in-part of U.S. application Ser. No. 08/335,475filed Nov. 7, 1994, now abandoned, and which (international application)is also a continuation-in-part of U.S. Ser. No. 08/484,974 filed Jun. 7,1995, now abandoned, which is a continuation-in-part of U.S. Ser. No.08/335,475 filed Nov. 7, 1994, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain substituted benzylamine derivativeswhich selectively bind to human Neuropeptide Y1 (NPY1) receptors. Thisinvention also relates to pharmaceutical compositions comprising suchcompounds. It further relates to the use of such compounds andcompositions in treating feeding disorders and certain cardiovasculardiseases.

2. Description of the Related Art

Neuropeptide Y, a peptide first isolated in 1982, is widely distributedin the central and peripheral neurons and is responsible for a multitudeof biological effects in the brain and the periphery. Various animalstudies have shown that activation of Neuropeptide Y₁ receptors isrelated to vasoconstriction, Wahlestedt et al., Regul. Peptides, 13:307-318 (1986), McCauley and Westfall, J. Pharmacol. Exp. Ther. 261:863-868 (1992), and Grundemar et al., Br. J. Pharmacol. 105: 45-50(1992); and to stimulation of consummatory behavior, Flood and Morley,Peptides, 10: 963-966 (1989). Leibowitz and Alexander, Peptides, 12:1251-1260 (1991), and Stanley et al., Peptides, 13: 581-587 (1992).

Grundemar and Hakanson, TiPS, May 1994 Vol. 15!, 153-159, state that, inanimals, Neuropeptide Y is a powerful stimuli of food intake, and aninducer of vasoconstriction leading to hypertension. They further pointout that low levels of Neuropeptide Y is associated with loss ofappetite. These reports clearly indicate that compounds that inhibit theactivity of this protein will reduce hypertension and appetite inanimals.

SUMMARY OF THE INVENTION

Compounds that interact with NPY1 receptors and inhibit the activity ofNeuropeptide Y at those receptors are useful in treating eatingdisorders such as, for example, obesity and bulimia, and certaincardiovascular diseases, such as, for example, hypertension.

This invention provides novel compounds of Formula I which selectivelybind to Neuropeptide Y₁ (NPY1) receptors. Such compounds are useful intreating feeding disorders such as obesity and bulimia as well ascertain cardiovascular diseases such as essential hypertension.

The invention also provides pharmaceutical compositions comprisingcompounds of Formula I. The invention thus further relates to the use ofsuch compounds and compositions in the treatment of eating as well ascertain cardiovascular diseases. Accordingly, a broad embodiment of theinvention is directed to a compound of Formula I: ##STR2## where Ar isan aryl group

B is sulfur, oxygen, a substituted nitrogen atom, or a mono- ordisubstituted carbon atom;

n is 1,2, or 3;

m is 2, 3, or 4;

W, X, Y, and T are the same or different and represent hydrogen,halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

R₁ and R₂ independently represent hydrogen, or straight or branchedchain lower alkyl having 1-6 carbon atoms; and

R₃ and R₄ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms.

These compounds are highly selective partial agonists or antagonists athuman NPY1 receptors and are useful in the diagnosis and treatment offeeding disorders such as obesity and bulimia as well as certaincardiovascular diseases such as essential hypertension and congestiveheart failure.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by general formula I: ##STR3## where Ar is an aryl grouppreferably selected from the group consisting of phenyl, 2-, 3-, or4-pyridyl, 2- or 3-thienyl, 2-, 4- or 5-pyrimidyl, each of which isoptionally mono- or disubstituted with halogen, hydroxy, or straight orbranched chain lower alkyl having 1-6 carbon atoms;

B is sulfur, oxygen, N(R₅) or C(R₅)(R₆);

n is 1, 2, or 3;

m is 2, 3, or 4;

W, X, Y, and T are the same or different and represent hydrogen,halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

R₁ and R₂ are the same or different and represent hydrogen, or straightor branched chain lower alkyl having 1-6 carbon atoms;

R₃ and R₄ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₅ represents straight or branched chain lower alkyl having 1-6 carbonatoms. phenyl, 2-, 3-, or 4-pyridyl, or phenyl, 2-, 3-, or 4-pyridylstraight or branched chain lower alkyl having 1-6 carbon atoms; and

A and R₆ are the same or different and represent

hydrogen, hydroxyl, amino, straight or branched chain lower alkyl having1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, phenoxy, 2- 3-, or 4-pyridyloxy, or

--(CH₂)_(p) --A'--(CH₂)_(q) --B' where

p is 0-5, q is 1-5, and A' is a direct bond, oxygen or sulfur, and

B' is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, straight or branched chain lower alkoxy having 1-6 carbon atoms,phenyl, 2-, 3-, or 4-pyridyl, phenoxy, 2-, 3-, or 4-pyridyloxy,carboxyl, carboalkoxy, carboxamido, mono or dialkylcarboxamido, amino,or mono or dialkylamino.

Preferred compounds according to Formula I are those where Ar isoptionally substituted phenyl, pyrimidinyl or pyridyl, B is carbonoptionally substituted with phenyl or alkyl, and W, X, Y, A, T, andR1-R₄ are hydrogen. Particularly, preferred compounds or Formula I arethose where Ar is phenyl, pyrimidinyl or pyridyl, B is carbon optionallysubstituted with phenyl or alkyl, and W, X, Y, A, T, and R₁ -R₄ arehydrogen.

The invention also relates to compounds of formula IA: ##STR4## where Aris phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 2-, 4- or 5-pyrimidyl,each of which is optionally mono- or disubstituted with halogen,hydroxy, or straight or branched chain lower alkyl having 1-6 carbonatoms;

A, W, X, Y, and T are the same or different and represent hydrogen,halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

R₁ and R₂ are the same or different and represent hydrogen, or straightor branched chain lower alkyl having 1-6 carbon atoms;

R₃ and R₄ are the same or different and represent hydrogen, straight orbranched chain lower all having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; and

R₉ represents hydrogen, straight or branched chain lower alkyl having1-6 carbon atoms, phenyl.

The invention further encompasses compounds of Formula II: ##STR5##where A and X independently represent alkoxy and Ar represents phenyl,pyrimidinyl, or pyridyl.

Preferred compounds of Formula II are those where X and A are methoxy,ethoxy, isopropoxy, or butoxy, and Ar represents phenyl, pyrimidinyl, orpyridyl.

The invention further includes compounds of Formula III: ##STR6## whereX and A independently represent alkoxy and R₇ and R₈ are different andrepresent hydrogen or fluorine.

The invention further encompasses compounds of Formula IV: ##STR7##where X represents hydroxy and Ar represents phenyl, pyrimidinyl, orpyridyl.

The invention further encompasses compounds of Formula V: ##STR8## whereX represents alkoxy and Ar represents phenyl, pyrimidinyl, or pyridyl.

Preferred compounds of Formula V are those where X is methoxy, ethoxy,isopropoxy, or butoxy, and Ar represents phenyl. Particularly preferredcompounds of Formula V are those where X is methoxymethoxy orethoxymethoxy.

The invention also includes compounds of Formula VI: ##STR9## where Xrepresents alkoxy, R₉ is alkyl, and Ar represents phenyl, pyrimidinyl,or pyridyl.

Preferred compounds of Formula VI are those where X is methoxy, ethoxy,isopropoxy, or butoxy, R₉ is alkyl, and Ar represents phenyl.Particularly preferred compounds of Formula VI are those where X ismethoxy, ethoxy, isopropoxy, or butoxy, R₉ is methyl, and Ar representsphenyl. Other particularly preferred compounds of Formula VI are thosewhere X is methoxymethoxy or ethoxymethoxy, R₉ is methyl, and Arrepresents phenyl.

The invention also encompasses compounds of Formula VII: ##STR10## whereAr represents optionally substituted phenyl, pyrimidinyl, or pyridyl.

Preferred compounds of Formula Ar represents phenyl, pyrimidinyl, orpyridyl.

Representative compounds of the present invention, which are encompassedby Formula I-VII, include, but are not limited to the compounds in FIG.I and their pharmaceutically acceptable salts. Non-toxicpharmaceutically acceptable salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

The invention also relates to compounds of formula VIII: ##STR11## whereAr is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 2-, 4- or5-pyrimidyl, each of which is optionally mono- or disubstituted withhalogen, hydroxy, or straight or branched chain lower alkyl having 1-6carbon atoms;

A, X, Y, and T are the same or different and represent hydrogen,halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; and

R₉ represents hydrogen, straight or branched chain lower alkyl having1-6 carbon atoms, or phenyl.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I-VIII. Those skilled in the art will recognizevarious synthetic methodologies which may be employed to preparenon-toxic pharmaceutically acceptable addition salts and acylatedprodrugs of the compounds encompassed by Formula I.

The invention encompasses both diasteriomers of the compounds having1,4-substitution on the cyclohexane ring. I.e., the inventionencompasses both cis-, and trans-1,4-cyclohexanes. Preferred compoundsof the invention having 1,4-substitution on the cyclohexane ring arethose where the nitrogen atom forming the piperazine ring and the alkylor phenyl group in the 4-position of the cyclohexane ring are "cis" withrespect to each other. Thus, preferred compounds of the invention havingsuch substitution are those that are cis-1-piperazinyl-4-alkyl orphenyl-cyclohexanes.

By "aryl" and "Ar" is meant an aromatic carbocyclic group having asingle ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), whichcan optionally be unsubstituted or substituted with e.g., halogen, lowerall, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By "alkyl" and "lower alkyl" is meant straight and branched chain alkylgroups having from 1-6 carbon atoms.

By "lower alkoxy" and "alkoxy" is meant straight and branched chainalkoxy groups having from 1-6 carbon atoms.

By "halogen" is meant fluorine, chlorine, bromine and iodine.

By 2-, 3-, and 4-pryidyloxy is meant groups of the following formulasrespectively: ##STR12##

The pharmaceutical utility of compounds of this invention is indicatedby the following assay for human NPY1 receptor activity.

Assay for Human NPY1 receptor binding activity

The procedure used is similar to that described by Gordon et al. (J.Neurochem. 55:506-513, 1990). SK-N-MC cells were purchased from ATCC(Rockville, Md.). Cells were maintained at 37° C. and 5% CO₂ inDulbecco's modified essential media (DMEM) with L-glutamine and 110 mg/Lsodium pyruvate, which was supplemented with 10% fetal bovine serum and25 mM HEPES (pH 7.3). The binding assay was performed in 24-well plates(Falcon) when the cells were confluent. Taking care to not disturb thecells on the bottom of the wells, the media was aspirated, and 0.5 ml ofDulbecco's phosphate buffered saline (DPBS) with calcium and magnesiumwere added to each well. The DPBS was aspirated and an additionalaliquot of DPBS was added and aspirated. To begin the assay, bindingbuffer consisting of serum-free DMEM containing 0.5% bovine serumalbumin, 0.1% bacitracin and 0.1 mM phenylmethylsulfonylfluoride wasadded to each well. The cells and the binding buffer preincubated for 30minutes at room temperature, at which point the drug dilution and ¹²⁵I!PYY (NEN-DuPont: 50000-75000 cpm-50 pM) were added to yield a finalvolume of 250 ul. Nonspecific binding was defined with 1 mM NPY (porcineor human, Bachem Calif.). After a 3 hour incubation at room temperature,the plates were then put on ice and the wells were aspirated. The cellswere washed 4-6 times with 0.5 ml of ice-cold DPBS. A dilute solution ofTriton X-100 (1%) was then added to each well. After approximately 1hour at room temperature, an aliquot from each well was transferred to a12×75 mm testtube, and the amount of ¹²⁵ I! was quantitated on a gammacounter with an efficiency of 80-85% (Genesys 5000, LaboratoryTechnologies). IC₅₀ values were calculated with the non-linear curvefitting program RS/1 (BBN Software Products Corp., Cambridge, Mass.).The binding characteristics for compounds of this invention are shown inTable 1.

                  TABLE I    ______________________________________    Compound Number  IC.sub.50 (μM)    ______________________________________    9                0.137    13 (cis isomer)  0.067    18 (cis isomer)  0.075    20 (cis isomer)  0.076    21 (trans isomer)                     0.525    29 (cis isomer)  0.039    ______________________________________

Compounds 13, 18, 20 and 29 are particularly preferred embodiments ofthe present invention because of their potency in binding to human NPY1receptors.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

An illustration of the preparation of compounds of the present inventionis given in Scheme I. Those having skill in the art will recognize thatthe starting materials may be varied and additional steps employed toproduce compounds encompassed by the present invention. ##STR13## whereA is ArN or ArCH where Ar is phenyl, 2, 3, or 4 pyridyl, 2 or 3 thienyl,2, 4 or 5 pyrimidyl either unsubstituted or mono or disubstituted withhalogen, hydroxy, or straight or branched chain lower alkyl having 1-6carbon atoms;

B is sulfur, oxygen NR₅ or CR₅ R₆

n is 1, 2, or 3;

m is 2, 3, or 4;

W, X, Y, Z, T are the same or different and represent hydrogen, halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms;

R₁ and R₂ are the same or different and represent hydrogen, or straightor branched chain lower alkyl having 1-6 carbon atoms;

R₃ and R₄ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₅ represents straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, 2, 3, or 4 pyridyl, or phenyl, 2, 3, or 4 pyridylstraight or branched chain lower alkyl having 1-6 carbon atoms;

E and R₆ are the same or different and represent hydrogen, hydroxyl,amino, straight or branched chain lower alkyl having 1-6 carbon atoms,straight or branched chain lower alkoxy having 1-6 carbon atoms, phenyl,2, 3, or 4 pyridyl, phenyloxy, 2, 3, or 4 pyridyloxy, or --(CH₂)_(p)--A'--(CH₂)_(q) --B' where p represents 0-5 and q represents 1-5 and A'is a direct bond, oxygen or sulfur and B' is hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, straight or branchedchain lower alkoxy having 1-6 carbon atoms, phenyl, 2, 3, or 4 pyridyl,phenyloxy, 2, 3, or 4 pyridyloxy, carboxyl, carboalkoxy, unsubstituted,mono or dialkylcarboxamido, amino, or mono or dialkylamino.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures and compounds described in them.

EXAMPLE I ##STR14##

1-Phenylpiperazine (11.3 mL, 12 g, 75 mmol) was suspended in 100 mLwater. The pH was adjusted to 3 using 10% HCl. Cyclohexanone (7.8 mL,7.4 g, 75 mmol) was added followed by KCN (5 g, 75 mmol). The mixturewas stirred 15 hours at room temperature during which time the productsolidified. The product was collected by filtration, washed with water,then recrystallized from ethanol to give 14.5 g of1-Cyano-1-(4-phenylpiperazin-1-yl)-cyclohexane as a white solid (73%yield), mp=133-135° C.

EXAMPLE II ##STR15##

1-Cyano-1-(4-phenylpiperazin-1-yl)-cyclohexane (300 mg, 1.1 mmol) wasdissolved in 10 mL ether under N2 at room temperature. Phenyl magnesiumbromide (4 mL of a 3 M ether solution) was added and the reactionmixture stirred 15 hours. The mixture was diluted with 10 mL ether,transferred to a separatory funnel, washed 1×10 mL saturated NH₄ Clsolution, then extracted 3×10 mL 5% HCl solution. The acidic extractswere basified using concentrated NH₄ OH solution then extracted 3×15 mLether. The organic extracts were filtered through a silica gel pad thenconcentrated to afford 280 mg of the free base of the desired compoundas a white solid (80% yield). This material was dissolved in 5 mL ethylacetate. Ethyl acetate saturated with HCl (5 mL) was added.1-Phenyl-1-(4-phenyl-piperazin-1-yl)-cyclohexane dihydrochloride(Compound 1) which precipitated out of solution (88 mg) was collected byfiltration, washed with ethyl acetate and dried in vacuo.

EXAMPLE III

The following compounds were prepared essentially according to theprocedure described in Examples I-II:

a) 1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexanedihydrochloride (Compound 2).

b) 1-(3-Methoxyphenyl)-1- 4-(2-pyrimidinyl)-piperazin-1-yl!-cyclohexanedihydrochloride (Compound 3).

c) 1-(3-Methoxyphenyl)-1- 4-(2-pyridinyl)-piperazin-1-yl!-cyclohexanedihydrochloride (Compound 4).

d) 1-(3-Methoxyphenyl)-1- 4-(2-fluorophenyl)-piperazin-1-yl!-cyclohexanedihydrochloride (Compound 5).

e) 1-(3-Methoxyphenyl)-1- 4-(4-fluorophenyl)-piperazin-1-yl!-cyclohexanedihydrochloride (Compound 6).

f) 1-(3-Hydroxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexanedihydrochloride (Compound 7).

g) 1-(3, 5-Dimethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexanedihydrochloride (Compound 8).

h) 1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexanedihydrochloride (Compound 9).

i) 1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-phenyl-cyclohexanedihydrochloride (cis isomer: Compound 10, trans isomer Compound 11).

j) 1-(3-n-Butoxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexanedihydrochloride (Compound 12).

k) 1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexanedihydrochloride (cis isomer: Compound 13, trans isomer: Compound 14).

l) 1-(4-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexanedihydrochloride (Compound 15).

m) 1-(2-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexanedihydrochloride Compound 16).

n) 1-(3,4-Methenedioxyphenyl)-1-(4-phenylpiperazin-1-yl)cyclohexanedihydrochloride (Compound 17).

o) 1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexanedihydrochloride (cis isomer: Compound 18, trans isomer: Compound 19).

p) 1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-ethyl-cyclohexanedihydrochloride (cis isomer: Compound 20, trans isomer: Compound 21).

q)1-(3-Isopropoxyphenyl-1-yl)-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexanedihydrochloride(cis isomer: Compound 22, trans isomer: Compound 23).

r) 1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-3-methyl-cyclohexanedihydrochloride (cis isomer: Compound 24, trans isomer: Compound 25).

s) 1-(3-Benzyloxyphenyl)-1-(4-phenylpiperazin-1-yl)-cyclohexanedihydrochloride (Compound 26).

t) 4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin-1-yl)-tetrahydropyrandihydrochloride (Compound 27).

u) 4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin-1-yl)-tetrahydrothiopyrandihydrochloride (Compound 28).

v)1-(3-Methoxymethoxyphenyl)-1-(4-phenylpiperazin-yl)-4-methyl-cyclohexanedihydrochloride (cis isomer: Compound 29, trans isomer: Compound 30).

w)1-(3-Ethoxymethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexanedihydrochloride(cis isomer: Compound 31, trans isomer: Compound 32).

x) 1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methoxy-cyclohexanedihydrochloride (cis isomer: Compound 33, trans isomer: Compound 34).

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claim. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound selected from the group consistingof:both diastereomers of1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane;both diastereomers of1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane; bothdiastereomers of1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-ethyl-cyclohexane; bothdiastereomers of1-(3-Isoproxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane;4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin-1-yl)-tetrahydropyran; and4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin 1-yl)-tetrahydrothiopyran. 2.The compound of claim 1 which is both diasteromers of1-(3-Methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane. 3.The compound of claim 1 which is both diastereomers of1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane. 4.The compound of claim 1 which is both diastereomers of1-(3-Ethoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-ethyl-cyclohexane. 5.The compound of claim 1 which is both diastereomers of1-(3-Isopropoxyphenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane.6. The compound of claim 1 which is4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin-1-yl)-tetrahydropyran.
 7. Thecompound of claim 1 which is4-(3-Ethoxyphenyl)-4-(4-phenylpiperazin-1-yl)-tetrahydrothiopyran.
 8. Apharmaceutical composition comprising an amount of a compound of claim 1effective for inhibition of NPY1 receptors and a pharmaceuticallyacceptable carrier.